A common practice in clinical oncology is to treat patients with the highest tolerable dose of drug so as to maximize its tumoricidal effects. Our studies have shown that in some situations a low dose of drug might be as effective as a high dose of drug yet be associated with far fewer side effects. We have cured mice bearing a large s.c. or i.p. MOPC-315 tumor load and extensive splenic metastases by administering a single injection of a low dose of CY which is less than one-tenth of the maximal tolerable dose. The curative effect of the low dose of drug is due to cooperation between the toxic effects of CY and antitumor immunity in tumor eradication. Such cooperation is also obtained when a low dose of CY is administered to mice with suppressed antitumor immune responsiveness. In this situation, the immunosuppression is overcome and immunopotentiating activity appears resulting in the generation of augmented levels of antitumor immunity that can aid effectively in tumor eradication. Our observations are not limited to the MOPC-315 tumor model and a low dose of CY. A low dose of melphalan which is less than one-tenth of the maximal tolerable dose of drug can also cure mice bearing a large MOPC-315 tumor in cooperation with antitumor immunity. In addition, a low dose of CY in cooperation with antitumor immunity is effective in curing mice at advanced stages of growth of another plasmacytoma, the MOPC-104E. Thus, our results indicate that it is important to consider not only the tumoricidal effects of the drug but also its effect on the immune system in developing an optimal protocol for chemotherapy.